Endogenous Bufadienolides, Fibrosis and Preeclampsia

Abstract

Frequency of preeclampsia has no tendency to decrease, and it still takes the leading position in the structure of maternal mortality and morbidity worldwide. In this review, we present the “fibrotic concept” of the etiology and pathogenesis of preeclampsia which involves system consisting of Na/K-ATPase and its endogenous ligands including marinobufagenin. New therapy of preeclampsia includes modulation of the Na/K-ATPase system by immunoneutralization of the marinobufagenin and use of mineralocorticoid antagonists which are capable to impair marinobufagenin-Na/K-ATPase interactions.

Depth of the Steroid Core Location Determines the Mode of Na,K-ATPase Inhibition by Cardiotonic Steroids

“…At least three CTSs (ouabain, marinobufagenin and telocinobufagin) were found in human plasma and/or urine [1][2][3][4]; besides that, several digoxin-immunoreactive compounds were also revealed [5,6]. It was demonstrated that the increase in the endogenous CTSs concentration in human and animal blood may be involved in the development of preeclampsia, chronic kidney disease, hypertension and other cardiovascular diseases [7][8][9][10][11][12]. Changes in the marinobufagenin level can affect both vessel cells and blood cells, notably altering the Na,K-ATPase activity of erythrocytes [13].…”

Endogenous Digitalis-like Factors as a Key Molecule in the Pathophysiology of Pregnancy-Induced Hypertension and a Potential Therapeutic Target in Preeclampsia

“…The cornerstone in the pathogenesis of preeclampsia is the abnormal remodeling of uterine spiral arteries and their subsequent fibrosis by various vascular factors, including cardiotonic steroids [ 95 ]. Recent research demonstrated that in addition to the vasoconstrictor effects of CS, these compounds directly affect intracellular signaling resulting in vascular fibrosis and impaired vasorelaxation [ 96 ].…”

“…There is substantial evidence that the profibrotic effect of MBG is attributed to another intracellular pathway, the EGFR-Src-dependent inhibition of Fli-1, a nuclear transcription factor, and a negative collagen-1 regulator [ 95 ]. The Na + /K + -ATPase/Src/EGFR complex activates signaling, which results in the phosphorylation of PKCδ and its translocation to the nucleus, then PKCδ phosphorylates Fli-1, which withdraws the Fli1-induced inhibition of the Col1 promoter and increases procollagen expression and collagen-1 production [ 100 ].…”

“…Two possible treatment approaches are investigated for neutralizing the negative effects of EDLF in preeclampsia—immunoneutralization and antagonism against receptor [ 95 ] ( Figure 1 ). Major of the evidence of the efficacy of this approach is based on in vitro studies and animal models of preeclampsia.…”

“…As spironolactone administration is associated with the feminization of male fetuses, its administration during pregnancy may not be suitable [ 126 ]. In animal studies, eplerenone, another mineralocorticoid antagonist, has not been associated with adverse reactions during pregnancy [ 95 ]. While data on its use in human pregnancy are lacking, future studies may be warranted.…”